Dysregulated APP expression and α-secretase processing of APP is involved in manganese-induced cognitive impairment

Yiping Yang; Jie Zhang; Xiaobo Yang; Zhiying Li; Jian Wang; Cailing Lu; Aruo Nan; Yunfeng Zou

doi:10.1016/j.ecoenv.2021.112365

Dysregulated APP expression and α-secretase processing of APP is involved in manganese-induced cognitive impairment

Ecotoxicol Environ Saf. 2021 Sep 1:220:112365. doi: 10.1016/j.ecoenv.2021.112365. Epub 2021 May 28.

Authors

Yiping Yang¹, Jie Zhang², Xiaobo Yang³, Zhiying Li², Jian Wang³, Cailing Lu⁴, Aruo Nan⁵, Yunfeng Zou⁶

Affiliations

¹ Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, Guangxi, China.
² Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China.
³ Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China.
⁴ Department of Nutrition and Food Hygiene, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China.
⁵ Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China. Electronic address: nanaruo@163.com.
⁶ Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, Guangxi, China. Electronic address: zouyunfeng@gxmu.edu.cn.

PMID: 34058678
DOI: 10.1016/j.ecoenv.2021.112365

Abstract

Excessive exposure to manganese (Mn) can cause cognitive impairment, a common feature of Alzheimer's disease (AD), but the mechanisms remain unclear. Amyloid precursor protein (APP) is key to AD pathogenesis, and whether APP and its secretase processing are involved in Mn-induced cognitive impairment remains unknown. In the present study, we established a model of Mn-induced neurotoxicity in vivo (male C57BL/6, 0-100 mg/kg Mn, 90 days, gastric gavage) and in vitro (Neuro-2a (N2a) cells, 0-800 μM Mn for 24 h; APP overexpression and APP shRNA N2a cells, 0 and 800 μM Mn for 24 h). We found impaired cognition of Mn-treated mice. Both in vivo and in vitro results consistently showed that Mn exposure inhibited the expression of APP, α-secretase, soluble APP alpha protein (sAPPα), and synapse proteins as well as the activity of α-secretase. However, Mn exposure showed no effect on the protein levels of β-secretase, Aβ40, and Aβ42 or the activity of β-secretase. Collectively, these findings demonstrate key roles of APP and its α-secretase processing in the regulation of Mn-induced cognitive impairment, which may act as a target for ameliorating Mn-induced neurotoxicity.

Keywords: APP; Cognitive impairment; Mn; Synaptic deficit; α-secretase; β-secretase.

MeSH terms

Amyloid Precursor Protein Secretases / genetics
Amyloid Precursor Protein Secretases / metabolism*
Amyloid beta-Protein Precursor / genetics
Amyloid beta-Protein Precursor / metabolism*
Animals
Cell Line
Cognitive Dysfunction / chemically induced*
Cognitive Dysfunction / metabolism
Cognitive Dysfunction / pathology
Male
Manganese / toxicity*
Mice
Mice, Inbred C57BL
Synapses / drug effects
Synapses / metabolism
Synapses / pathology

Substances

Amyloid beta-Protein Precursor
Manganese
Amyloid Precursor Protein Secretases